ES2615236T3 - Treatment of viral infections - Google Patents

Abstract

Stable composition for the treatment of lesions associated with herpes viral infections, where the composition is in the form of creams and gels that contain a low concentration of trichloroacetic acid, the amount of trichloroacetic acid being less than 6% (m / m) of the mass of the cream or gel.

Description

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DESCRIPTION

Treatment of African infections

The present invention refers to the treatment or control of African infections. In particular, but not exclusively, the invention refers to the treatment of viral infections of the herpes type, including in particular herpes simplex I, herpes simplex II and herpes zoster.

The human being himself is the reservoir of herpesvirus hominis. It has been described in a study that antibodies to the herpes virus have been found in 30-37% of university students, 62% of private patients and more than 80% of outpatient patients. Although the virus is carried as a latent infection in most individuals, in others an acute exacerbation of the activated virus occurs, in a variety of ways, and can be precipitated by a variety of factors, including traumatic factors such as sunlight , menstruation, and family setbacks. It is believed that cold sores or blisters are caused by herpes simplex I, while it is believed that herpes simplex II is the agent in genital herpes infections.

Herpes zoster (or simply zoster) causes the skin disease commonly known as shingles. It is a African disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in the form of a strip. Initial infection with the chickenpox-zoster virus (VZV) causes acute and short-lived chickenpox disease, and usually occurs in children and young people. Once an episode of chickenpox has resolved, the virus is not eliminated from the body but can last and cause shingles, which has different symptoms, often many years after the initial infection.

The varicella-zoster virus can become dormant in nerve cell bodies, and less frequently in non-neuronal satellite cells of the spinal, cranial, or autonomic ganglion without causing any symptoms. In an immunocompromised individual, perhaps years or decades after chickenpox infection, the virus can leave the cell bodies and travel through the neuronal axons to cause African skin infections in the nerve region. The virus can spread from one or more nodes along the nerves of an affected segment and infect the corresponding dermatome (an area of the skin supplied by a spinal nerve), causing a painful rash. Although the rash usually heals over a period of two to four weeks, some people who suffer from this condition experience residual nerve pain for months or years. This condition is called postherpetic neuralgia. Exactly it is not understood exactly how the virus remains latent in the organism and subsequently re-activates.

The global incidence rate of herpes zoster is placed every year in a range of 1.2 to 3.4 cases per 1,000 healthy individuals, increasing to 3.9-11.8 per year per 1,000 individuals among those over 65 years. Treatment with antiviral drugs can reduce the severity and duration of herpes zoster, if a treatment of seven to ten days of these drugs is started within 72 hours after the onset of the characteristic rash. The amino acid lysine, which is a component of the proteins that take place in natural food products, is described in the literature as an anti-herpetic agent.

A striking feature of herpes infections is their appearance in patients known to have an appreciable titer of herpes antibodies. The presence of antibodies is therefore not a guarantee of protection against acute outbreaks. The route of infection of the herpes virus seems to be through direct contact, as can occur between sexual partners, mothers and children and even a dentist.

Oral herpes can take the form of recurrent lip lesions. Some patients have severe oral lesions that cause considerable difficulty eating. It has been estimated that up to one third of the population has recurrent episodes of oral infection and that more than half of these patients have more than one episode each year. Herpes group viruses also cause serious illness in patients with immunological deficiencies, for example patients with HIV infections, and particularly in patients who are being treated for cancer with drugs with immunosuppressive properties.

Ocular herpes and herpetic encephalitis are additional forms of infection with the herpes virus that require intensive and continuous medical attention that does not incorporate the treatment described. Genital herpes, which had an incidence of 100,000 cases in the US In 1973, it was estimated that by 1980 it had affected 30% of the sexually active population. The problem of herpes infections is therefore a serious and growing problem.

The present invention provides the use of trichloroacetic acid in the preparation of a medicament for the treatment of African infections by the topical administration of an effective amount of the medicament to a person or animal in need of treatment.

The trichloroacetic acid compositions of the prior art have been presented in the form of liquids or fine gels that are easily drained after application. The applicant knows the report WO 00/71105 (A2) (from Mezzoli), Acid

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trichloroacetic for the preparation of solutions and / or compositions for the treatment of erosive and / or ulcerative lesions, which represents the prior art closest to the present invention known to the applicant. Mezzoli describes the use of aqueous solutions of trichloroacetic acid for the treatment of erosive and / or ulcerative lesions in which the concentrations of trichloroacetic acid in the aqueous solution are in a range of a minimum of 10% to a maximum of 90 %, preferably from 10% to 50% and more preferably from about 50%. Mezzoli indicates (see page 5, lines 12 and 13) that trichloroacetic acid solutions with concentrations below 30% are unstable and must be used in a very short period of time. Mezzoli also describes formulations of trichloroacetic acid in alcohol and ether, and indicates that the higher the concentration of trichloroacetic acid, the more active the solution is, the shorter the treatment period and the smaller the number of topical applications per day required. Mezzoli describes topical applications that vary from one to three times a day and describes that minor aphthous ulcerative lesions disappear in a period of one to three days, and the lesions heal in a period of two to four days. In the case of ulcerative lesions of major sores, Mezzoli describes that the pain and signs of inflammation disappear in a period of three to five days and that the injury heals in a period of seven to eight days. Ulcerative or erosive lesions of the mucous membrane or complexion treated topically with Mezzoli liquid trichloroacetic acid in aqueous solution, or with pharmaceutical compositions comprising the same, become whitish due to the action of trichloroacetic acid in the lesion, and in the mucosa and complexion around the lesion. The action of the trichloroacetic acid and the whitish color due to the action increase in intensity with the increase in the concentration of trichloroacetic acid in the aqueous solution or the pharmaceutical composition.

WO 97/09963 discloses a method for treating the skin of a human patient without subjecting the patient to light radiation. The method employs a composition containing a maximum of 30% trichloroacetic acid, a visualizing agent and a surfactant to treat the skin of a patient with skin peeling.

The applicant has observed, surprisingly, that a formulation in the form of a cream or gel, containing only 5% trichloroacetic acid is very effective for the treatment of herpes lesions despite the belief commonly held among experts doctors who deal with the treatment of such injuries, that a 5% trichloroacetic acid concentration in a pharmaceutical formulation is ineffective. The results obtained with the formulation of the present invention are therefore unexpected, in the light of the widely held view that formulations containing low concentrations of trichloroacetic acid would be ineffective for the treatment of herpes lesions.

According to a first aspect of the invention, a stable composition is provided for the treatment of lesions associated with viral herpes infections, where the composition is in a selected form between creams and gels and which contains a low concentration of trichloroacetic acid, where The amount of trichloroacetic acid is less than 6% (m / m) of the mass of the cream or gel.

The abbreviation "% (m / m)" refers to the mass percentage of trichloroacetic acid in a given mass of the composition. By "low concentration" in the context of this specification, a trichloroacetic acid concentration is understood to be less than 6% and, preferably, between about 2.5 and 5% (m / m). By "stable composition" is meant a composition that is stable for at least 12-18 months. It had been observed that prior art compositions containing less than 30% trichloroacetic acid are substantially less stable, with a shelf life of less than about 6 months.

The amount of trichloroacetic acid may be between about 1% and 5.5% (m / m), preferably between about 1.5% and 5% (m / m) and more preferably between about 2.5 % and 5.0% (m / m). In a preferred embodiment of the invention, the composition is in the form of a cream and the amount of trichloroacetic acid in the cream is approximately 5% (m / m). In another preferred embodiment of the invention, the composition is in the form of a gel and the amount of trichloroacetic acid in the gel is approximately 2.5%.

An advantage of the composition of the invention is that the low concentration of trichloroacetic acid will allow the composition to be marketed as a medicament not subject to medical prescription that can be safely applied by the buyer and will not require to be administered by an expert therapist. . A second important advantage of the invention is that because the composition is in the form of a cream or gel it can be easily and accurately applied to an injury. Prior art formulations such as Mezzoli, are fine fluids or gels that cannot be applied precisely and tend to drain and therefore come into contact with the skin around the lesion. Because these liquids or fine gels have concentrations of trichloroacetic acid that are much higher than the concentration of the composition of the invention, they affect the skin in the area around the lesion causing abrasion and scaling. The composition of the invention can be applied precisely in an injury and will not be drained under the influence of gravity, so that it remains in the place where it is applied for the duration of the treatment. Because it can be applied precisely and does not drain, the composition of the invention generally needs to be applied only once, following which the lesion dries and quickly heals with minimal scaling over a period of 24 to 48 hours. Prior art formulations, such as the Mezzoli formulation, require one to three

treatments per day for a period of two to four days, and abrasion and peeling around the injury occurs. The applicant is an expert in the area of the invention and knows that the Mezzoli process has not been successful and would be a painful and very inconvenient process. The applicant is also of the opinion that higher concentrations of trichloroacetic acid would prevent Mezzoli formulations from being sold as drugs not subject to medical prescription.

The composition may include pharmaceutically acceptable excipients, selected from viscosity formers, humectants (or humidifying agents), emulsifiers, chelating agents or mixtures thereof. Emulsifiers are components that help keep the oil and water phases stable in an emulsion such as a cream.

The viscosity former may be selected from xanthan gum, hydroxypropyl guar, magnesium aluminum silicate, hydroxyethylcellulose and mixtures of two or more thereof. The humectant may be selected from propylene glycol, butylene glycol, pentylene glycol, glycerin, sorbitol and mixtures of two or more thereof. The emulsifiers can be selected from fatty alcohols, polyethylene glycol ethers of fatty acids, glycerol esters of long chain fatty acids, polyethylene glycol esters of long chain fatty acids and mixtures thereof. The chelating agent may be selected from ethylenediaminetetraacetic acid (EDTA), preferably as its sodium salt, tetrasodium glutamate diacetate, ethylenediamine-N acid, N'-disuccinic acid (EDDS) and mixtures of two or more thereof.

The fatty alcohol may be a C16-C18 alcohol such as cetearyl alcohol (or ketostearyl) alcohol. The polyethylene glycol ether of the fatty alcohol can be ceteareth-20. The glycerol ester may be glyceryl stearate. The polyethylene glycol ester 20 may be polyethylene oxide stearate such as PEG-40 stearate.

In one embodiment of the invention, the composition may contain approximately 0.5% to 6.0% (m / m) of trichloroacetic acid, approximately 5% to 15% (m / m) of the emulsifier, from about 0.2% to 1.2% (m / m) of xanthan gum, about 1% to 5% (m / m) of propylene glycol and about 0.25% to 0, 35% (m / m) of EDTA as sodium salt.

The composition may contain approximately 0.3% (m / m) of EDTA.

In another embodiment of the invention, the composition may contain between 1.0% and 5% (m / m) of trichloroacetic acid and may be used in a gel with slow drying properties.

The African infection may be an infection with the herpes virus and may, in particular, be an infection caused by herpes simplex I, herpes simplex II or herpes zoster.

30 The applicant has observed that the medicament of the invention is effective in the treatment of lesions of the lips, mouth, gums, genitals, trunk and limbs when applied as a cream. The applicant is aware that herpes infections can be stopped in the early stages by lowering the skin's pH to a pH value of approximately 2. The applicant is also aware that trichloroacetic acid at lower concentrations is well tolerated by of body tissues, and surrounding tissues are not damaged by a short exposure to trichloroacetic acid. Paradoxically, it is known that higher concentrations of trichloroacetic acid worsen herpes infections. The applicant has now observed that all herpes lesions can be treated and stopped by the application of a trichloroacetic acid composition, such as a cream containing between 1% and 5% trichloroacetic acid or a gel that It contains approximately 2.5% trichloroacetic acid.

For a topical application, the trichloroacetic acid is preferably dispersed in the form of a fine powder in a conventional cream base at a concentration of between about 0.5% and about 5% (m / m), preferably about 5 %. The cream is freely applied to the affected parts and spread gently by rubbing it to penetrate the tissues. Applications can be made once or, for serious infections, every 12 hours for one to two days. The cream form can also be used for topical applications intrabucally and intravaginally. The applicant knows that the herpes virus must first bind to a receptor on the surface of the cell before it can penetrate it. This requires intra-cellular alkalinization, and if there is a change in pH towards acidosis then the virus cannot bind and replicate. This prevents the infection from spreading. The applicant believes that the low dose of trichloroacetic acid of the invention works in this way and provides an effective, convenient and cost-effective treatment of an infection with the herpes virus. The change in the pH of the skin caused by the topical application of the acid is in effect responsible for the therapeutic effects.

The advantages of the invention can be summarized as follows. The formulation of the invention in the first place is not a solution, but a cream that can be used easily and safely by the final consumer, while the compositions of the prior art are liquids that can only be used by clinicians.

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experts The cream of the invention does not cause pain and at most causes a slight stinging sensation while the prior art formulation stings and produces abrasion to a large extent and can be extremely uncomfortable. The cream of the invention is also stable and does not drain while prior art products in the form of solutions or gels easily drain onto the surface of the skin due to gravity and affect the skin adjacent to the lesion being treated. .

The cream of the invention can also be easily packaged in small packages such as tubes that allow easy dispensing of small amounts of the cream, while prior art formulations are generally packaged in bottles from which solutions are not readily dispensed. . The cream of the invention is also not dangerous if spilled, while the formulations of the prior art are potentially erosive acidic liquids. The skin surrounding the lesion may come into contact with the cream of the invention, but due to the low concentration of trichloroacetic acid in the cream, the surrounding skin is not affected while the prior art formulations damage the surrounding skin, cause the death of cells and a potentially deep peeling. Because the surrounding skin is protected by its surface barrier properties of the stratum corneum (corneal layer), which is not destroyed by the low concentration of trichloroacetic acid, the cells of the basal keratinocyte (growing) layer of the epidermis (layer upper skin) are not destroyed and thus the healing process is accelerated. Higher concentrations of trichloroacetic acid, as seen in prior art formulations, destroy the epidermis barrier and allow damage to the deepest layer of growing cells and delay healing.

The cream of the invention is stable for at least one year and thus lends itself to the sale without medical prescription, while prior art formulations such as the formulation described in Mezzoli are unstable if the concentration of trichloroacetic acid is lower. of 30%. In addition, the action time is four to five minutes for the cream, while for prior art formulations with high concentrations the exposure time is measured in seconds. Even if the cream of the invention is used incorrectly, for example, it is left on the skin for ten minutes, the applicant has observed that there are no harmful effects either. If prior art formulations such as that of Mezzoli are used to "double" expose the skin, serious complications may arise and such exposure may result in severe scarring.

The cream of the invention generally requires a single application, after which the lesion dries and it is generally not necessary for the cream to be used in successive days. The prior art formulations require one to three treatments per day until the wound is healed and this process lasts two to four days. In the process of healing the invention, the lesion dries and barely peels, while in the case of prior art formulations, peeling is a significant component of the healing phase. In addition, the cream of the invention does not require a specific type of applicator and can be easily applied with the fingertip, while the prior art formulation described by Mezzoli requires a specific type of applicator (see for example claims 12, 13 and 14 of Mezzoli).

The invention is described below by way of example in reference to the following Examples.

Example 1

In different embodiments of the invention, gels or creams were prepared using trichloroacetic acid (1% to 5% m / m), EDTA disodium chelating agents or tetrasodium glutamate diacetate (0.05 to 2% m / m) , the emulsifier glyceryl stearate (0.5 to 10% m / m) or the emulsifiers cetearyl alcohol, glyceryl stearate, PEG-40 stearate and ceteareth-20 (1 to 10% m / m), the former of xanthan gum viscosity (0.1 to 1% m / m), propylene glycol humectants (0.5 to 5% m / m) and water (100%). Tetrasodium glutamate dicacetate can be obtained in stores.

For the elaboration of the cream, the components were weighed in a calibrated digital scale. Depending on the size of the lot, a Mettler scale from Meltter Toledo model PB 3002-5 was used for smaller lots. The various components were mixed in stainless steel containers or plastic buckets.

Xanthan gum and propylene glycol were first mixed to form a paste and the paste was added to a part of the water and mixed thoroughly with a Silverson homogenizer to hydrate the xanthan gum. PEG-100 glyceryl stearate and cetearyl alcohol, glyceryl stearate, PEG-40 stearate and ceteareth-20 were weighed and heated on a 80 ° C heated plate in a copper-bottomed stainless steel vessel. A digital thermometer was used to measure the temperature.

Chelating agent, disodium EDTA and the emulsifiers of glyceryl stearate, cetearyl alcohol, glyceryl stearate, PEG-40 stearate and ceteareth-20 were added to the volume of water at 80 ° C, and homogenized with a Silverson homogenizer at high speed ( usually from 50,000 to 60,000 rpm) for 2-5 minutes depending on the size of the batch to produce an emulsion. The gum was added to the emulsion and the mixture was homogenized at medium speed (usually at approximately 25,000 rpm) to produce a homogeneous material.

The material was allowed to cool naturally to <50 ° C. The active ingredient trichloroacetic acid, dissolved in an equal amount of fine water, was added while homogenizing at medium speed (usually at 25,000 rpm) until the mixture became bright.

Example 2

5 Treatment of Herpes I (Herpes Simplex) and Herpes II (Genital Herpes)

The affected skin area was cleaned and the cream containing 2.5% prepared trichloroacetic acid as described in Example 1 was applied in a small amount of the size of a pea (larger size for more extensive lesions ) to cover the infected area. The cream was applied in an amount sufficient to produce an opaque white layer on the lesion. The cream was left on the skin for 4 minutes and then washed with water. The lesions changed significantly drying and producing a slight scab. If necessary, the lesions were treated again in the same way after a 24-hour period.

Example 3

Herpes Zoster Treatment

The affected skin area was cleaned and the cream containing 2.5% trichloroacetic acid prepared as described in Example 1, was applied with a soft brush to cover the infected area. The cream was left on the skin for 4-10 minutes and then washed with water. The lesions changed significantly by drying them. The lesions were treated again in the same way after a 24-hour period. If there was a minimal change in the lesions and they remained uncomfortable, an application was reapplied after 12 hours of and then again after 24 hours. The treatments were repeated daily until it was evident that the lesion had stabilized. Generally, a maximum of four days is needed for herpes Zoster.

Claims (12)

5 10 fifteen twenty 25 30 1. Stable composition for the treatment of lesions associated with herpes vinca infections, where the composition is in the form of creams and gels that contain a low concentration of trichloroacetic acid, the amount of trichloroacetic acid being less than 6% (m / m) of the mass of the cream or gel. 2. Composition according to claim 1, wherein the amount of trichloroacetic acid is between 1.0% (m / m) and 5.5% (m / m). 3. Composition according to claim 2, wherein the composition is in the form of a cream and the amount of trichloroacetic acid in the cream is 5% (m / m). 4. Composition according to claim 2, wherein the composition is in the form of a gel and the amount of trichloroacetic acid in the gel is 2.5%. 5. Composition according to any one of claims 1 to 4, which includes pharmaceutically acceptable excipients, selected from viscosity formers, emulsifiers, chelating agents and mixtures thereof. 6. Composition according to claim 5, wherein the viscosity former is selected from xanthan gum, hydroxypropyl guar, magnesium aluminum silicate, hydroxyethylcellulose and mixtures of two or more thereof. 7. Composition according to any one of claims 4 to 6 inclusive, wherein the humectant is selected from propylene glycol, butylene glycol, pentalenglycol, glycerin, sorbitol and a mixture of two or more thereof. 8. Composition according to any one of claims 4 to 7 inclusive, wherein the emulsifiers are selected from fatty alcohols, polyethylene glycol ethers of fatty alcohols, glycerol esters of long chain fatty alcohols, polyethylene glycol esters of chain fatty acids long and mixtures of two or more thereof. 9. Composition according to any of claims 4 to 8 inclusive, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), salts of ethylenediaminetetraacetic acid, tetrasodium glutamate diacetate, ethylenediamine-N acid, N'-disuccphnic acid (EDDS) ) and mixtures of two or more thereof. 10. Composition according to claim 9, containing from 0.5% to 6.0% (m / m) of trichloroacetic acid, from 5% to 15% (m / m) of the emulsifier, of 0 , 2% to 1.2% (m / m) of xanthan gum, from 1% to 5% (m / m) of propylene glycol and from 0.25% to 0.35% (m / m) from EDTA as its sodium salt. 11. Composition according to claim 9 or 10, wherein the fatty alcohol is cetearyl alcohol, the polyethylene glycol ether of the fatty alcohol is ceteareth-20, the glycerol ester of the long chain fatty acid is glyceryl stearate and the ester of Long-chain fatty acid polyethylene glycol is PEG-40 stearate. 12. Composition according to any of the preceding claims, wherein the trichloroacetic acid is dispersed in the cream or gel in the form of a fine powder.